Project Summary/Abstract Obesity is a major cause of morbidity and mortality within our VA medical system accounting for the majority of cases of diabetes mellitus, hypertension, coronary artery disease and cerebrovascular accidents. An improved understanding of the regulation of body weight in our veteran obese patients will improve the quality of life by avoidance of serious medical complications and by suggesting novel therapeutic approaches. The objective of this study is to establish that a high protein diet is efficacious, safe and beneficial to curtail food intake and body weight in obese patients and to establish the neurohormonal mechanisms of high protein diet-induced early satiety signal in relevant experimental model, focusing on activation of gastric vagal afferents. We will assess the efficacy of a high protein diet on satiety and pattern of postprandial gut hormone in obese patients. A randomized controlled study lasting 24-30 months will assign volunteer subjects (ages e30, BMI 27-40 kg/m2) to: 1) Very high protein diet group, 2) High protein diet group, and 3) Standard protein diet group as control with same calories. All the subjects will be followed by a dietitian and determination of circulating gut hormone and biochemical assays will be performed. Neurohumoral mechanisms through which high protein diet curtailed food intake will be assessed by testing the hypthesis of a potentiating effect of gut peptides released by high protein on vagal afferent satieting signaling to the brain in obese rats using pharmacologica and electrophysiologic approaches. In addition Fos immunohistochemistry to map brain neuronal activation in respone to high protein diet will allow us to establish differential circuitries activated by high vs standard protein diet. These studies will provide a clinical basis on the weight reducing effect of high protein diet and the associated alterations in the profile of postprandial gut hormones released, and unravel the underlying mechanisms at the neuronal (vagal afferent) level in an expermental model of obesity. The proposed studies will address important pathophysiological questions regarding the mechanisms regulating satiety/body weight as well as provide potentially important clinical treatment strategies.